POS0393 ASSOCIATION BETWEEN GENETICALLY PREDICTED EXPRESSION OF TPMT AND AZATHIOPRINE ADVERSE EVENTS IN PATIENTS WITH INFLAMMATORY CONDITIONS
Authors: A. Davis, A. Dickson, L. Daniel, P. Nepal, J. Zanussi, T. Miller-Fleming, P. Straub, W. Q. Wei, G. Liu, N. Cox, A. Hung, Q. Feng, C. M. Stein, C. P. Chung
Journal: Annals of the Rheumatic Diseases (2022)

Background Azathioprine is a widely used immunosuppressant for the treatment of inflammatory conditions such as systemic lupus erythematosus (SLE), systemic vasculitis, dermatomyositis, and inflammatory bowel disease. However, its use is often limited by myelotoxicity. Variants in the gene encoding thiopurine-S-methyltransferase (TPMT), an enzyme in the metabolic pathway of azathioprine, increase the risk for myelotoxicity 1 . We know little about the relationship between the genetically predicted expression of TPMT and side effects of azathioprine. Objectives To examine whether genetically predicted expression of TPMT in liver tissue is associated with azathioprine adverse effects. Methods We assembled a retrospective cohort of new users taking azathioprine for inflammatory conditions at a tertiary care center. We performed genotyping with Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content data, and we then used Michigan Imputation servers for genetic imputation and PrediXcan models trained with GTEx/Genotype-Tissue Expression Project version 8 data to impute TPMT expression in liver tissue. We prespecified nine groups of phecodes (comprised of ICD9 and ICD10 codes) corresponding to known adverse effects of azathioprine. We then tested the association between the predicted expression of TPMT and these adverse events; for outcomes significant in the Wilcoxon ranksum tests (p&lt;0.05), each case was reviewed in clinical records for confirmation. Finally, we grouped the predicted expression of TPMT in liver tissue into tertiles and conducted logistic regressions to assess the associations between predicted expression and side effects. We conducted a sensitivity analysis restricted to patients with EHR-reported White race. Results The cohort included 1034 patients (Table 1). Phecodes for 3 side effects—leukopenia (n=29), skin cancer (n=13), and rash (n=52)—were identified as associated with predicted TPMT expression in liver tissue. Of these, cases of side effects attributed to azathioprine were validated by chart review: leukopenia (96.6%; n=28), skin cancer (92.3%; n=12), and rash (9.6%; n=5) and used for analysis. When assessed by tertile of predicted TPMT expression, patients in the highest tertile had lower odds of having leukopenia (OR=0.35, 95%CI: 0.12-0.98, p=0.045) and a trend towards higher odds for skin cancer, but the number of cases was small (OR=3.56, 95%CI: 0.73-17.27, p=0.115). Confirmed cases of rash attributed to azathioprine were too few for meaningful analysis. We found similar results when restricted to patients with reported White race. Table 1. Characteristics of patients by TPMT expression Lowest Tertile Middle Tertile Highest Tertile N=345 N=345 N=344 Female sex, n (%) 228 (66.1) 244 (70.7) 238 (69.2) EHR-reported White race, n (%) 306 (88.7) 293 (84.9) 290 (84.3) Age, median [IQR] 42 [29-58] 43 [30-55] 46 [30-56] Indication, n (%) Systemic lupus erythematosus 38 (11.0) 42 (12.2) 38 (11.0) Inflammatory bowel disease 191 (55.3) 185 (53.6) 190 (55.2) Other connective tissue disorder/autoimmune 92 (26.7) 96 (27.8) 100 (29.1) Other 24 (7.0) 22 (6.4) 16 (4.7) Verified leukopenia attributed to azathioprine, n (%) 14 (4.1) 9 (2.6) 5 (1.5) Verified skin cancer attributed to azathioprine, n (%) 2 (0.6) 3 (0.9) 7 (2.0) Verified rash attributed to azathioprine, n (%) 2 (0.6) 3 (0.9) 0 (0) Conclusion This analysis suggests that PrediXcan may be useful for examining the association between gene expression and side effects of medications. Moreover, this approach successfully identified leukopenia as a side effect associated with predicted TPMT expression. Acknowledgements None to declare. Disclosure of Interests None declared.